;Cr(VI) induces premature senescence through ROS-mediated p53 pathway in L-02 hepatocytes
;Cr(VI) induces premature senescence through ROS-mediated p53 pathway in L-02 hepatocytes
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Cr(VI) 通过 ROS 介导的 p53 通路诱导 L-02 肝细胞过早衰老
DOI：
10.1038/srep34578
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发表时间：
2016-10-04
影响因子：
4.6
通讯作者：
Xiao, Fang
中科院分区：
文献类型：
--
作者：
Zhang, Yujing;Zhang, Yiyuan;Xiao, Fang
六价铬 [Cr(VI)] 在冶金和纺织染色等行业有多种用途，可引起多种人类疾病，包括炎症和癌症。与之前关注 Cr(VI) 诱导的氧化损伤和细胞凋亡的研究不同，本研究重点关注低剂量和长期接触 Cr(VI) 可能诱发的过早衰老。我们发现 Cr(VI) 会诱导 L-02 肝细胞过早衰老，这一点通过衰老相关 β-半乳糖苷酶 (SA-β-Gal) 活性的增加得到证实。 Cr(VI) 通过 Ser15 磷酸化稳定 p53，并增加 p53 转录靶点 p21 的表达。机制研究表明，Cr(VI) 靶向并抑制线粒体呼吸链复合物 (MRCC) I 和 II，以增强活性氧 (ROS) 的产生。通过应用抗氧化剂Trolox，我们还证实ROS介导p53激活。使用含有 p53 shRNA 的四环素诱导慢病毒表达系统来敲除 p53。我们发现p53可以抑制促生存基因B细胞淋巴瘤-2（Bcl-2）、髓性白血病-1（Mcl-1）和S期相关细胞周期蛋白细胞周期蛋白依赖性激酶2（CDK2）、细胞周期蛋白E来诱导早衰，而ROS在Cr（VI）诱导的早衰中的功能作用取决于p53。结果表明，Cr(VI) 通过促进 L-02 肝细胞中 ROS 依赖性 p53 激活而在过早衰老中发挥作用。
Hexavalent Chromium [Cr(VI)], which can be found of various uses in industries such as metallurgy and textile dying, can cause a number of human disease including inflammation and cancer. Unlike previous research that focused on Cr(VI)-induced oxidative damage and apoptosis, this study placed emphasis on premature senescence that can be induced by low-dose and long-term Cr(VI) exposure. We found Cr(VI) induced premature senescence in L-02 hepatocytes, as confirmed by increase in senescence associated-β-galactosidase (SA-β-Gal) activity. Cr(VI) stabilized p53 through phosphorylation at Ser15 and increased expression of p53-transcriptional target p21. Mechanism study revealed Cr(VI) targeted and inhibited mitochondrial respiratory chain complex (MRCC) I and II to enhance reactive oxygen species (ROS) production. By applying antioxidant Trolox, we also confirmed that ROS mediated p53 activation. A tetracycline-inducible lentiviral expression system containing shRNA to p53 was used to knockout p53. We found p53 could inhibit pro-survival genes B-cell lymphoma-2 (Bcl-2), myeloid leukemia-1 (Mcl-1) and S phase related cell cycle proteins cyclin-dependent kinase 2 (CDK2), Cyclin E to induce premature senescence, and the functional role of ROS in Cr(VI)-induced premature senescence is depend on p53. The results suggest that Cr(VI) has a role in premature senescence by promoting ROS-dependent p53 activation in L-02 hepatocytes.